Project Summary: About 40% of the mammalian genome is made up of interspersed repetitive DMA which consists mainly of the 'fossil remains'of parasitic genetic elements such as retrotransposons. The most common class of mammalian retrotranposons is L1. L1s have major mutagenic impacts on the genomes in which they reside, causing unique types of DNA shuffling and transcriptional control throughout these genomes. By mechanisms that are not understood, active elements within a species tend to be very closely related. Active L1s are a feature of almost every mammalian genome examined, but we have identified two cases where they have ceased movement. Both their global distribution in mammals and the close relationship between active elements in a species are very different from patterns seen in L1-related elements of non-mammalian hosts. This proposal takes a broad comparative approach to understand which features of L1 biology are general across mammals, which features are exceptions to the rules, and what these exceptions can teach us about L1s. This proposal has three Specific Aims: Aim 1 -To examine patterns of L1 activity and extinction in mammals: i. to estimate the frequency of L1 extinction in mammals;ii. to statistically determine if there is a deficiency in early L1 extinctions;iii. to determine the processes of L1 evolution that give rise to multiple, long-term L1 lineages. Aim 2 - To determine whether L1 extinction is consistently correlated with expansion of another retrotransposon family. Aim 3 - To examine the relationship between CpG methylation and L1 activity / extinction: i. to estimate the rate of mutation at methylated CpG sites on the autosomes and sex chromosomes;ii. to determine the relationship between CpG content of L1 elements and L1 activity levels, subfamily structure and host genome composition;iii. to determine whether transgenerational disruption of methylation is correlated with increased retrotransposition. Relevance: This is a basic research proposal aimed at understanding the ongoing role of L1 elements in shaping our genome. This research will explore factors that maintain active L1s in most genomes and at the same time constrain their diversification, and will estimate human mutation rates in light of the apparent mutational bias at CpG sites on the X chromosome. This proposal will also ask whether changes in patterns of methylation by endocrine disruptors is linked to increased rates of retrotransposition.